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Nature. 2018 Aug;560(7717):192-197. doi: 10.1038/s41586-018-0356-z. Epub 2018 Jul 25.

Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis.

Author information

1
Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK.
2
Global Health R&D, GlaxoSmithKline, Tres Cantos, Spain.
3
David Jack Centre for R&D, GlaxoSmithKline, Ware, UK.
4
Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, UK.
5
Wellcome Sanger Institute, Cambridge, UK.
6
Centre of Immunobiology, Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
7
Cellzome GmbH, A GlaxoSmithKline Company, Heidelberg, Germany.
8
GlaxoSmithKline, New Frontiers Science Park, Harlow, UK.
9
Global Health R&D, GlaxoSmithKline, Stockley Park West, Uxbridge, UK.
10
Global Health R&D, GlaxoSmithKline, Tres Cantos, Spain. tim.j.miles@gsk.com.
11
Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK. k.read@dundee.ac.uk.
12
Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK. i.h.gilbert@dundee.ac.uk.

Abstract

Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis.

PMID:
30046105
PMCID:
PMC6402543
DOI:
10.1038/s41586-018-0356-z
[Indexed for MEDLINE]
Free PMC Article

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